Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors.
The role of the proteasome in neuronal apoptosis is poorly understood since both anti- and pro-apoptotic effects result from proteasome inhibition. We studied the effects of proteasome inhibition in cultured rat cerebellar granule neurons. Acute exposure to proteasome inhibitors MG-132 and lactacystin blocked caspase activation induced by removal of depolarizing medium. However, chronic treatment with MG-132 activated caspases in neurons maintained in depolarizing potassium. The biphasic effect of MG-132 was hypothesized to be due to differential degradation of anti- and pro-apoptotic proteins. Accordingly, acute exposure to MG-132 inhibited the hyperphosphorylation, loss of DNA binding, ubiquitination, and degradation of the pro-survival transcription factor MEF2D induced by removal of depolarizing medium. In contrast, chronic exposure to MG-132 increased the expression and phosphorylation of c-Jun, elevated levels of the pro-apoptotic protein Bim, and triggered neuronal apoptosis, even in the presence of depolarizing medium. Thus, proteasome inhibition exerts an acute pro-survival action by stabilizing MEF2 transcription factors. However, chronic proteasome inhibition causes a build-up of phosphorylated c-Jun and Bim, which eventually overwhelms the effects of MEF2 and triggers apoptosis.
Pubmed ID: 16112871 RIS Download
Animals | Animals, Newborn | Apoptosis | Cell Survival | Cerebellum | Gene Expression Regulation | Neurons | Polymerase Chain Reaction | Proteasome Endopeptidase Complex | Proteasome Inhibitors | Rats | Rats, Sprague-Dawley | Transcription Factors